Cycloartane-type triterpenoids from Combretum quadrangulare Kurz with PCSK9 secretion inhibitory activities.

Nine previously undescribed (1-9) and seven known (10-16) cycloartane-type triterpenoids were isolated and characterized from Combretum quadrangulare Kurz using physicochemical and spectroscopic methods. The absolute configurations of these compounds were determined through modified Mosher's method and quantum chemical calculation of electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra. Their inhibitory activities against PCSK9 secretion were assessed, and a plausible structure-activity relationship was delineated.

Dihydrostilbenes and flavonoids from whole plants of Jacobaea vulgaris.

The isolation of previously undescribed 12 compounds from the MeOH extract of Jacobaea vulgaris whole plants is disclosed, comprising 11 dihydrostilbenes (1-11) and one flavanone (12), and eight known compounds (six flavonoids, one dihydrostilbene, and one caffeoylquinic acid). Structural elucidation employed spectroscopic methods, including 1D and 2D NMR spectroscopy, HRESIMS, and ECD calculations. Evaluation of the compounds' effects on PCSK9 and LDLR mRNA expression revealed that compounds 1 and 3 downregulated PCSK9 mRNA while increasing LDLR mRNA expression, suggesting potential cholesterol-lowering properties.

No Interference of H9 Extract on Trastuzumab Pharmacokinetics in Their Combinations.

Trastuzumab is used to treat breast cancer patients overexpressing human epidermal growth factor receptor 2, but resistance and toxicity limit its uses, leading to attention to trastuzumab combinations. Recently, the synergistic effect of trastuzumab and H9 extract (H9) combination against breast cancer has been reported. Because drug exposure determines its efficacy and toxicity, the question of whether H9 changes trastuzumab exposure in the body has been raised.

Improved Pharmacokinetic Feasibilities of Mirabegron-1,2-Ethanedisulfonic Acid, Mirabegron-1,5-Naphthalenedisulfonic Acid, and Mirabegron-L-Pyroglutamic Acid as Co-Amorphous Dispersions in Rats and Mice.

Mirabegron (MBR) is a β-adrenoceptor agonist used for treating overactive bladder syndrome. Due to its poor solubility and low bioavailability (), the development of novel MBR formulations has garnered increasing attention. Recently, co-amorphous dispersions of MBR, such as MBR-1,2-ethanedisulfonic acid (MBR-EFA), MBR-1,5-naphthalenedisulfonic acid (MBR-NDA), and MBR-L-pyroglutamic acid (MBR-PG), have been developed, showing improved solubility and thermodynamic stability.

Stereochemical assignment of clerodane-type diterpenes from the fruits of Casearia grewiifolia and their ability to inhibit PCSK9 expression.

More than 20 natural products have been reported to modulate PCSK9-mediated cholesterol regulation, and small-molecule-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors continue to be developed and identified. Here, twelve undescribed clerodane-type diterpenes (1-9 and 12-14) and two known compounds were isolated from the chloroform-soluble extract of the dried fruits of Casearia grewiifolia Vent. using a PCSK9 mRNA expression monitoring assay.

Evaluation of Pharmacokinetic Feasibility of Febuxostat/L-pyroglutamic Acid Cocrystals in Rats and Mice.

Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II, showing low solubility and high permeability with a moderate value (<49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with an improving 4-fold increase of FBX solubility. Nevertheless, the in vivo pharmacokinetic properties of FBX-PG have not been evaluated yet.

Pharmacokinetic Feasibility of Stability-Enhanced Solid-State (SESS) Tenofovir Disoproxil Free Base Crystal.

Tenofovir (TEV) is a nucleotide reverse transcriptase inhibitor used against human immunodeficiency virus (HIV) reverse transcriptase. To improve the poor bioavailability of TEV, TEV disoproxil (TD), an ester prodrug of TEV, was developed, and TD fumarate (TDF; Viread) has been marketed due to the hydrolysis of TD in moisture. Recently, a stability-enhanced solid-state TD free base crystal (SESS-TD crystal) was developed with improved solubility (192% of TEV) under gastrointestinal pH condition and stability under accelerated conditions (40 °C, RH 75%) for 30 days.

Change of metformin concentrations in the liver as a pharmacological target site of metformin after long-term combined treatment with ginseng berry extract.

Metformin as an oral glucose-lowering drug is used to treat type 2 diabetic mellitus. Considering the relatively high incidence of cardiovascular complications and other metabolic diseases in diabetic mellitus patients, a combination of metformin plus herbal supplements is a preferrable way to improve the therapeutic outcomes of metformin. Ginseng berry, the fruit of Meyer, has investigated as a candidate in metformin combination mainly due to its anti-hyperglycemic, anti-hyperlipidemic, anti-obesity, anti-hepatic steatosis and anti-inflammatory effects.

Isocoumarins and Benzoquinones with Their Proprotein Convertase Subtilisin/Kexin Type 9 Expression Inhibitory Activities from Dried Roots of .

A phytochemical investigation of the -hexane-soluble chemical constituents roots allowed for selection using a proprotein convertase subtilisin-kexin type 9 (PCSK9) mRNA expression monitoring assay in HepG2 cells. This led to the isolation of two previously undescribed isocoumarins of natural origin, 8'Z,11'Z-octadecadienyl-6,8-dihydroxyisocoumarin () and 3-pentadecyl-6,8-dihydroxyisocoumarin (), along with 20 previously reported compounds (-). All of the structures were established using NMR spectroscopic data and MS analysis.

Suppression of Tumor Growth and Cell Migration by Indole-Based Benzenesulfonamides and Their Synergistic Effects in Combination with Doxorubicin.

Pharmacological inhibition of the enzyme activity targeting carbonic anhydrases (CAs) demonstrated antiglaucoma and anticancer effects through pH control. Recently, we reported a series of indole-based benzenesulfonamides as potent CA inhibitors. The present study aimed to evaluate the antitumor effects of these compounds against various cancer cell lines, including breast cancer (MDA-MB-231, MCF-7, and SK-BR-3), lung cancer (A549), and pancreatic cancer (Panc1) cells.

Chemical Constituents from the Roots and Rhizomes of and Their Effects on Proprotein Convertase Substilisin/Kexin Type 9 Expression.

This study was conducted to further investigate bioactive molecules from that can inhibit proprotein convertase substilisin/kexin type 9 (PCSK9) expression. After interpreting NMR spectroscopic data and MS spectral data of all isolates, a new naturally occurring compound, 6-hydroxy-vitexin-2″--rhamnoside (), was identified along with 30 known compounds. The calculation of the gauge-including atomic orbital (GAIO) and electronic circular dichroism (ECD) proposed the absolute configuration of as (2,3)-methyl-2-(4-hydroxybenzyl)tartrate by comparing the calculated ECD with experimental data.

Effect of Water Extract of Mangosteen Pericarp on Donepezil Pharmacokinetics in Mice.

The pharmacokinetic (PK) change in a drug by co-administered herbal products can alter the efficacy and toxicity. In the circumstances that herb-drug combinations have been increasingly attempted to alleviate Alzheimer's disease (AD), the PK evaluation of herb-drug interaction (HDI) is necessary. The change in systemic exposure as well as target tissue distribution of the drug have been issued in HDIs.

Salicinoyl Quinic Acids and Their Prostaglandin E Production Inhibitory Activities from the Fruits of .

Phytochemical investigation on the dried fruits of led to the identification of 10 new salicinoyl quinic acid derivatives (-), a new benzoyl quinic acid (), and two known compounds ( and ). The structures of the new compounds were elucidated by interpreting 1D and 2D NMR spectroscopic data including HMBC and EXSIDE along with a chemical method for sugar unit analysis. All isolates were evaluated for their inhibitory activities against prostaglandin E (PGE) production in ultraviolet B (UVB)-irradiated HaCat keratinocytes.

Identification of neolignans with PCSK9 downregulatory and LDLR upregulatory activities from Penthorum chinense and the potential in cholesterol uptake by transcriptional regulation of LDLR via SREBP2.

Ethnopharmacological Relevance: Penthorum chinense has been used in East Asia for the treatment of cholecystitis, infectious hepatitis, jaundice and to treat liver problems. Recent evidences provided the potential for the clinical use of P. chinense in the treatment of metabolic disease.

Dilignans with a Chromanol Motif Discovered by Molecular Networking from the Stem Barks of and Their Proprotein Convertase Subtilisin/Kexin Type 9 Expression Inhibitory Activity.

Natural products have been fundamental materials in drug discovery. Traditional strategies for observing natural products with novel structure and/or biological activity are challenging due to large cost and time consumption. Implementation of the MS/MS-based molecular networking strategy with the in silico annotation tool is expected to expedite the dereplication of secondary metabolites.

Erratum: Choi, Y.H., et al. Multifaceted Factors Causing Conflicting Outcomes in Herb-Drug Interactions. 2021, , 43.

The authors wish to make the following correction to the funding information [...

A Novel Integrated Pharmacokinetic-Pharmacodynamic Model to Evaluate Combination Therapy and Determine Synergism.

Understanding pharmacokinetic (PK)-pharmacodynamic (PD) relationships is essential in translational research. Existing PK-PD models for combination therapy lack consideration of quantitative contributions from individual drugs, whereas interaction factor is always assigned arbitrarily to one drug and overstretched for the determination of pharmacologic synergism. Herein, we report a novel generic PK-PD model for combination therapy by considering apparent contributions from individual drugs coadministered.

Sesquiterpenoids from the Aerial Parts of with Inhibitory Activities on Proprotein Convertase Subtilisin/Kexin Type 9 Expression.

Phytochemical investigation of the methanol extract of the aerial parts of aided by a proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA expression screening assay in HepG2 cells led to the identification of 19 compounds including one new norsesquiterpene (), six new eudesmane sesquiterpenoids (-, , and ), and 12 known compounds. The structures of all compounds were elucidated by interpretation of their 1D and 2D NMR spectroscopic and MS data. Furthermore, computational prediction of ECD or chemical shifts was used to propose the absolute configurations of the new structures.

Pharmacokinetic Properties of Moracin C in Mice.

Moracin C from fruits, also known as the mulberry, has been proven to exhibit inhibitory activities against lipoxygenase enzymes, TNF- and interleukin-1 secretion, and proprotein convertase subtilisin/kexin type 9 expression. Despite the various pharmacological activities of moracin C, its pharmacokinetic characteristics have yet to be reported. Here, the pharmacokinetic parameters and tissue distribution of moracin C have been investigated in mice, and the plasma concentration of moracin C with multiple dosage regimens was simulated via pharmacokinetic modeling.

Multifaceted Factors Causing Conflicting Outcomes in Herb-Drug Interactions.

Metabolic enzyme and/or transporter-mediated pharmacokinetic (PK) changes in a drug caused by concomitant herbal products have been a primary issue of herb and drug interactions (HDIs), because PK changes of a drug may result in the alternation of efficacy and toxicity. Studies on HDIs have been carried out by predictive in vitro and in vivo preclinical studies, and clinical trials. Nevertheless, the discrepancies between predictive data and the clinical significance on HDIs still exist, and different reports of HDIs add to rather than clarify the confusion regarding the use of herbal products and drug combinations.

Transcriptome Analysis Illuminates a Hub Role of in Cholesterol Metabolism by α-Mangostin.

Whole-transcriptome analysis of α-mangostin-treated HepG2 cells revealed that genes relevant to lipid and cholesterol metabolic processes responded to α-mangostin treatment. α-Mangostin downregulated a series of cholesterol biosynthetic genes, including , , and , and controlled specific cholesterol trafficking-associated genes such as , , and . In particular, the downregulation of expression highlighted SREBP2 as a key transcriptional factor controlling lipid or cholesterol metabolic processes.

RNA Drugs and RNA Targets for Small Molecules: Principles, Progress, and Challenges.

RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery.

Combination of and Metformin Ameliorates Diet-Induced Metabolic Dysregulation in Mice via the Gut-Liver-Brain Axis.

(SB), a herbal medicine, is commonly used to treat metabolic diseases, while Metformin (MF) is a widely used drug for type 2 diabetes. The purpose of this study was to investigate whether co-treatment of SB with MF could produce a potential therapeutic effect on high-fat and high-fructose diet (HFFD)-induced metabolic dysregulation. First, we optimized the dose of SB (100, 200, 400, and 800[Formula: see text]mg/kg) with MF (200[Formula: see text]mg/kg) in HFFD-induced C57BL6J mice.

A New Therapeutic Approach Using a Calcilytic (AXT914) for Postsurgical Hypoparathyroidism in Female Rats.

Postsurgical hypoparathyroidism is the most common complication of thyroid surgery. Conventional therapy with high-dose calcium and vitamin D can correct hypocalcemia but can increase the risk of hypercalciuria, renal stones, or ectopic calcification. The aim of the present study was to investigate the efficacy of a calcium-sensing receptor antagonist, also called a calcilytic (AXT914), in rat models of postsurgical hypoparathyroidism.